Acetylcholinesterase

From Proteopedia

proteopedia linkproteopedia link

spinqualitylabelsall models AChE Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Key Enzyme in the Nervous System

Acetylcholinesterase (AChE) is key enzyme in the nervous system of animals. By rapid hydrolysis of the neurotransmitter, acetylcholine (ACh), AChE terminates neurotransmission at cholinergic synapses. It is a very fast enzyme, especially for a serine hydrolase, functioning at a rate approaching that of a diffusion-controlled reaction. AChE inhibitors are among the key drugs approved by the FDA for management of Alzheimer's disease (AD). The powerful toxicity of organophosphorus (OP) poisons is attributed primarily to their potent AChE inhibitors.

Solution of the 3D structure of Torpedo californica AChE (TcAChE) in 1991 (Sussman et al. & Silman (1991)) opened up new horizons in research on an enzyme that had already been the subject of intensive investigation. The unanticipated structure of this extremely rapid enzyme, in which the active site was found to be buried at the bottom of a , lined by aromatic residues, led to a revision of the views then held concerning substrate traffic, recognition, and hydrolysis (Botti et al. Sussman & Silman (1999)). This led to a series of theoretical and experimental studies, which took advantage of recent advances in theoretical techniques for treatment of proteins, such as molecular dynamics and electrostatics, and of sitedirected mutagenesis, utilizing suitable expression systems.

Alzheimer’s disease (AD) is a debilitating brain disease that occurs in around 10% of the elderly and, as yet, there is no known cure. At present, the most widely used treatments consist are medications that attempt to increase the brain’s levels of ACh, whose levels decrease with onset of disease. These drugs work by interfering with AChE. Thus drugs that are mild inhibitors of AChE, like Tacrine, E2020 (Aricept) and the natural Chinese produce Huperzine appear to retard symptoms of AD.

spinqualitylabelsall models AChE Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image deep and narrow gorge </scene>, lined with aromatic residues, with the peripheral site at the top or lip of this gorge. Amazingly, there were no acidic or negatively charged residues anywhere in these 2 sites or along this gorge, as would be expected to help attract and bind the basic, positively charged ACh substrate, although are are some acidic residues nearby. Instead, bulky aromatic residues (These numbers are the sequential numbering of the residues, starting from the N-terminus, according to the Torpedo Californica form of the enzyme.) See: AChE inhibitors and substrates Selected 3D Structures of AChE 2ace This is the original solved structure for Torpedo Californica 1ea5 This is one of the highest quality representative X-ray structures in the PDB. 1eve The E2020 (Aricept) complex. 1ax9 Endrophonium complex. 1vot Complex with Huperzine, a Chinese folk medicine. 1fss Complex with snake venum toxin Fasciculin-II. 1vzj Model complex of the Cholinesterase tetramer. More structures can be obtained by searching for 'AChE' at the left.